Enolates enolate-carbonyl equilibration

The rate of enolate-carbonyl equilibration " is dependent on the forward and backward rates of proton exchange. Proton exchange from a carbon-based acid is known to be slower than that of a more electronegative atom donor (in particular, O and N atoms) . For a series of closely related molecules usually the more acidic a given molecule is, the faster the rate of proton transfer (high kreu note that thermodynamic and kinetic parameters are not related). For example, benzocyclobutanone (10) is less acidic and the rate of deprotonation is substantially slower (10 times) than the related benzocyclopentanone (12) due to its enolate (11) having unfavourable anti-aromatic character. Deprotonation of the simplest cyclobutanone (13) clearly does not lead to an unfavourable anti-aromatic enolate (14) . By assuming the internal strain of 14 is similar to that of 11, cyclobutanone (13) is evidently 10 " times more acidic than benzocyclopentanone (12). By the same vain, the more acidic propanone (15) has a faster rate of deprotonation (10 times) than the less acidic ethyl acetate (16) . ... 

The successful use of acetal-protected carbonyl groups as iminium ion terminators for the construction of alkaloids is typified by Heathcock and coworkers syntheses of Lycopodium alkaloids to wit, lyco-podine and lycodine (Figure 2). A model cyclization that constructs the a-, b- and c-ring nuclei of the Lycopodium alkaloids is shown in equation (3). Treatment of diacetal (17) (a 1 1 diastereomeric mixture at C-2) with 1.3 equiv. of 3 M hydrochloric acid in methanol at room temperature for 2 d gave a single tricycle (18) in 66% yield. The authors advance that only one of the diastereomeric iminium ions will cy-clize however, enolization allows equilibration of these intermediates (Scheme 11). Thus, while dia-stereomer (19) can readily cyclize, (20) has no low energy cyclization pathway available, and must epimerize prior to cyclization. Corroborative support for this argument is found in the fact that the separated diastereomers of a related system cyclize to the same extent. ... 

Ketones and aldehydes bearing a hydrogens are in equilibrium with their enol forms, although for simple ketones and aldehydes the carbonyl forms are greatly favored. This equilibrium is the keto—enol tautomerization. Equilibration with the enol form can be either acid- or base-catalyzed. The enol form can be favored in special cases. Esters and other acid derivatives also have acidic a hydrogens. LDA is a strong base that can be used to drive ketones, aldehydes, or esters completely to their corresponding enolates. 

A carbonyl compound with a hydrogen atom on its a carbon rapidly equilibrates with its corresponding enol (Section 8.4). This rapid interconversion between two substances is a special kind of isomerism known as keto-enol tautomerism, from the Greek Canto, meaning "the same," and meros, meaning "part." The individual isomers are called tautomers. 

Keto-enol tautomerism (Sections 8.4, 22.1) The rapid equilibration between a carbonyl form and vinylic alcohol form of a molecule. 

Although the conversion of an aldehyde or a ketone to its enol tautomer is not generally a preparative procedure, the reactions do have their preparative aspects. If a full mole of base per mole of ketone is used, the enolate ion (10) is formed and can be isolated (see, e.g., 10-105). When enol ethers or esters are hydrolyzed, the enols initially formed immediately tautomerize to the aldehydes or ketones. In addition, the overall processes (forward plus reverse reactions) are often used for equilibration purposes. When an optically active compound in which the chirality is due to an asymmetric carbon a to a carbonyl group (as in 11) is treated with acid or base, racemization results. If there is another asymmetric center in the molecule. 

Several investigations have addressed the synthesis of boryl eno-lates by carbonyl enolization. Kbster has examined in detail the thermal reaction of triethylborane with substituted ethyl ketones catalyzed by diethylboryl pivalate (58) (eq. [40]) (61). The boryl pivalate 58 is undoubtedly the active reagent in this system, and it is regenerated by the illustrated protonolysis (eq. [41]) (62). The vigorous conditions employed in this procedure probably result in the generation of the equilibrated boryl enolates. The enolate ratios obtained by way of this procedure are summarized in Table 18. 

Aldol reactions have also been used as a means of macrocychzation in total synthesis and were quite successful in some cases. However, over a broader spectrum of substrates, the results are unpredictable at best and yields and stereochemical outcome vary greatly. The predominant reasons are difficulties in selective enolate formation in multi-carbonyl compounds, competing and equilibrating retro-aldolizations—especially with polyketides, which often possess several aldol moieties—and intermolecular instead of intramolecular reaction preference. Whereas most of these drawbacks may be overcome, substrate-independent stereocontrol plays a crucial role. At least one new stereocenter is formed during a macroaldolization, and because of the folding constraints involved, its configuration cannot be adequately predicted. Therefore, this can be useful in special cases but with the current possibilities is not the method of choice for a general diversity-oriented synthesis. 

The abstraction of a proton a to a carbonyl group is not the only method for generating enolates and these alternative methods also offer possibilities for regio- and stereoselectivity. Thus, cleavage of silyl enol ethers (e.g., 1 and 3)9, 12 17 and enol acetates (e.g., 5)18 has been used for the generation of specific enolates. The conditions for these cleavages have to be chosen so that there is no equilibration of the lithium enolates formed. 

C-Carboxylation of enolates.1 Carboxylation of potassium enolates generated from silyl enol ethers is not regioselective because of extensive enolate equilibration. Regiospecific C-carboxylation of lithium enolates is possible with carbonyl sulfide in place of carbon dioxide. The product is isolated as the thiol methyl ester. If simple esters are desired, transesterification can be effected with Hg(OAc)2 (8, 444). Carboxylation of ketones in this way in the presence of NaH and DMSO is not satisfactory because of competing alkylation of the enolate.2 Example ... 

The driving force for the neutral or anionic Oxy-Cope Rearrangement is that the product is an enol or enolate (resp.), which can tautomerize to the corresponding carbonyl compound. This product will not equilibrate back to the other regioisomer. 

Some of the reactions of PO3- parallel enzymatic reactions promoted by adenosine triphosphate (ATP). Pyruvate kinase catalyzes the equilibration of ATP and pyruvate with adenosine diphosphate (ADP) and phosphoenol pyruvate (11,12). In a formal sense, this reaction resembles the preparations of enol phosphate (eqs. 6 and 7). Cytidine triphosphate synthetase catalyzes the reaction of uridine triphosphate with ammonia to yield cytidine triphosphate (13). In a formal sense, this reaction resembles the replacement of the ester carbonyl group of ethyl acetate by the nitrogen of aniline (eq. 8). 

In alcohols, rate-limiting proton addition to the enol ether double-bond yields an alkoxycarbenium ion which can react with alcohol and with the small amounts of water contained in alcohols (59). For simple alcohols, since alcohol and water have comparable reactivities, acetal is formed predominantly as the kinetic product. Subsequent equilibration with the carbonyl compound usually occurs more slowly (El-Alaoui, 1979). 

Evidence for equilibration of carbonyl compounds with enols... 

In the equilibrium method, the carbonyl compound(s) must be treated with weak, usually aqueous or alcoholic, acid or base and allowed to equilibrate with all possible enols or enolates. Either only one product is possible (due to symmetry or blocking of a positions) or some thermodynamic factor (such as the formation of a stable conjugated enone) ensures that the reaction goes down one preferred route. 

The kinetic reprotonation by a series of carbonyl-based acids, of the lithium enolate obtained from 2,4-dimethyltetralone either by LDA-mediated deprotonation or by cleavage of its silyl enol ether, was studied by Eames (Scheme 71)352. The diastereoselective ratio, close to the thermodynamic value, obtained with methanol (pKa = 29 in DMSO) is probably due to equilibration. The difference observed in the presence of an additive was interpreted as the result of a fine balance between the coordinating ability, the intrinsic acidity, and probably the concentration of the enolic form of the cyclic and linear dicarbonyl acidic compounds. 

The kinetically controlled nucleophilic addition of preformed lithium enolates onto carbonyl compounds is reversible with a low activation barrier, and the thermal conditions are likely to have a major impact on the stereoisomeric ratio of the final aldols through the retroaldolization and the thermodynamic equilibration of lithium enolates76. The tendency of aldolates to undergo retroaldolization increases with the stability of enolates, and when going from lithium to potassium. On the other hand, boron enolates usually undergo completely irreversible aldol reaction511,512. 

EXAMPLE 10.8 Enols, compounds with an OH group directly bonded to a vinyl carbon, are normally less stable than the corresponding carbonyl ( keto ) isomer. [A few enols (e.g., phenols) exist predominantly or exclusively in the end form.] Though the uncatalyzed equilibration of enols with their keto isomers is usually slow, the rate of isomerization increases dramatically in the presence of a small amount of acid (HA) or base (B) ... 

Carbonyl compounds with hydrogens bonded to their a carbons equilibrate with their corresponding enols. 

A thermodynamic enolate is favored by equilibrating conditions. This is often achieved using a strong base in a protic solvent. A strong base yields both enolates, but in a protic solvent, enolates can also be protonated to re-form the carbonyl starting material. At equilibrium, the lower energy intermediate always wins out, so that the more stable, more substituted enolate is present in higher concentration. Thus, the thermodynamic enolate is favored by ... 

---